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| United States Patent |
6,099,862
|
|
Chen
, et al.
|
August 8, 2000
|
Oral dosage form for the controlled release of a biguanide and
sulfonylurea
Abstract
A controlled release pharmaceutical tablet containing antihyperglycemic
drug and a hypoglycemic drug that does not contain an expanding or gelling
polymer layer and comprising a core containing the antihyperglycemic drug
and the hypoglycemic drug, a semipermeable coating membrane surrounding
the core and at least one passageway in the membrane to allow the drugs to
be released from the core.
| Inventors:
|
Chen; Chih-Ming (Davie, FL);
Cheng; Xiu Xiu (Davie, FL);
Chou; Joseph (Coral Springs, FL);
Jan; Steve (Coral Springs, FL)
|
| Assignee:
|
ANDRX Corporation (Fort Lauderdale, FL)
|
| Appl. No.:
|
143876 |
| Filed:
|
August 31, 1998 |
| Current U.S. Class: |
424/473; 424/468; 424/474; 424/475; 424/479; 424/480 |
| Intern'l Class: |
A61K 009/24; A61K 009/36; A61K 009/20 |
| Field of Search: |
424/464,468,472,473,474,475,479,480
604/890.1,892.1
|
References Cited
U.S. Patent Documents
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| 4963141 | Oct., 1990 | Eckenhoff.
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| 5024843 | Jun., 1991 | Kuczynski et al.
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| 5030452 | Jul., 1991 | Curatolo.
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| 5071607 | Dec., 1991 | Ayer et al.
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| 5082668 | Jan., 1992 | Wong et al.
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| 5091190 | Feb., 1992 | Kuczynski et al.
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| 5108756 | Apr., 1992 | Curatolo.
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| 5110597 | May., 1992 | Wong et al.
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| 5120548 | Jun., 1992 | McClelland et al.
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| 5141752 | Aug., 1992 | Ayer et al.
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| 5178867 | Jan., 1993 | Guittard et al.
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| 5185158 | Feb., 1993 | Ayer et al.
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| 5260275 | Nov., 1993 | Cooper et al.
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| 5308348 | May., 1994 | Balaban et al.
| |
| 5356913 | Oct., 1994 | Colca.
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| 5413572 | May., 1995 | Wong et al.
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| 5543156 | Aug., 1996 | Roorda et al.
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| 5545413 | Aug., 1996 | Kuczynski et al.
| |
| 5591454 | Jan., 1997 | Kuczynski et al.
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| 5614578 | Mar., 1997 | Dong et al.
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| 5629319 | May., 1997 | Luo et al.
| |
| 5631224 | May., 1997 | Efendic et al.
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| 5650170 | Jul., 1997 | Wright et al.
| |
| 5667804 | Sep., 1997 | Wong et al.
| |
| 5668117 | Sep., 1997 | Shapiro.
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| 5674900 | Oct., 1997 | Ubillas et al.
| |
| 5688518 | Nov., 1997 | Ayer et al.
| |
| 5691386 | Nov., 1997 | Inman et al.
| |
| Foreign Patent Documents |
| 0283369 | Aug., 1993 | EP.
| |
| 2320735 | Aug., 1975 | FR.
| |
| 1522179 | Nov., 1976 | GB.
| |
| 9608243 | Mar., 1996 | WO.
| |
| 9609823 | Apr., 1996 | WO.
| |
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| |
| 9810786 | Mar., 1998 | WO.
| |
| 9827982 | Jul., 1998 | WO.
| |
| 99/03477 | Jan., 1999 | WO.
| |
Other References
Diem, Drug Therapy of Type-II Diabetes: Tablets, Insulin or a Combination
of These, Schweizerische Rundschau Fur Medizin Praxis, 83(2) pp68-71, Jan.
18, 1994.
Clin. Ther. 1996 May; 18 (3) : pp. 360-371.
By Briscoe TA, et al.; Dept. of Medicine Morehouse School of Medicine;
Altanta, GA.
Ann. Intern Med. 1998 Feb. 1; 128 (3) pp. 165-175.
Physician's Desk Reference 52th Edition pp. 795-800; 1217-1219; and
2182-2186.
|
Primary Examiner: Page; Thurman K.
Assistant Examiner: Seidleck; Brian K.
Attorney, Agent or Firm: Hedman, Gibson & Costigan, P.C.
Claims
We claim:
1. A controlled release pharmaceutical tablet which consisting essentially
of:
(a) a core consisting essentially of:
(i) metformin or a pharmaceutically acceptable salt thereof;
(ii) glipizide
(iii) polyvinyl pyrrolidone; and
(iv) sodium lauryl sulfate;
(b) optionally a seal coat around the core,
(c) a semipermeable membrane coating covering said core comprising:
(i) cellulose acetate;
(ii) polyethylene glycol with an average molecular weight between 380 and
420; and
(iii) a plasticizer; and
(d) at least one passageway in the semipermeable membrane to allow the
release of the metformin and glipizide from the core to the environment of
use to provide therapeutic levels of metformin and glipizide from twelve
to twenty-four hour periods.
2. A controlled release pharmaceutical tablet as defined in claim 1 that
exhibits the following dissolution profile when tested in a USP type 2
apparatus, paddle, at 75 rpms in 900 ml of simulated intestinal fluid, pH
7.5 phosphate buffer and at 37.degree. C.:
after 2 hours 0-30% of the metformin is released;
after 4 hours 10-50% of the metformin is released;
after 8 hours 30-90% of the metformin is released;
after 12 hours not less than 50% of the metformin is released; and
after 16 hours not less than 60% of the metformin is released; and
after 2 hours 0-30% of the glipizide is released;
after 4 hours 10-50% of the glipizide is released;
after 8 hours 30-90% of the glipizide is released;
after 12 hours not less than 50% of the glipizide is released; and
after 16 hours not less than 60% of the glipizide is released.
3. A controlled release pharmaceutical tablet as defined in claim 1 that
exhibits the following dissolution profile when tested in a USP type 2
apparatus at 75 rpms in 900 ml of simulated intestinal fluid, pH 7.5
phosphate buffer and at 37.degree. C.:
after 2 hours 0-25% of the metformin is released;
after 4 hours 20-45% of the metformin is released;
after 8 hours 45-90% of the metformin is released;
after 12 hours not less than 60% of the metformin is released; and
after 16 hours not less than 70% of the metformin is released; and
after 2 hours 0-25% of the glipizide is released;
after 4 hours 20-45% of the glipizide is released;
after 8 hours 45-90% of the glipizide is released;
after 12 hours not less than 60% of the glipizide is released; and
after 16 hours not less than 70% of the glipizide is released.
4. A controlled release pharmaceutical tablet as defined in claim 1 wherein
the plasticizer is triacetin.
Description
BACKGROUND OF THE INVENTION
The present invention relates to controlled release unit dose formulations
containing an antihyperglycemic drug and a hypoglycemic drug. As used in
this specification the term "antihyperglycemic" refers to a drug that is
useful in controlling or managing noninsulin-dependent diabetes mellitus
(NIDDM) by decreasing hepatic glucose production, decreasing intestinal
absorption of glucose and/or improving insulin sensitivity. Biguanides are
the preferred antihyperglycemic drugs. As used in this specification the
term "hypoglycemic" refers to a drug that is useful in controlling or
managing noninsulin-dependent diabetes mellitus (NIDDM) by stimulating the
release of insulin from the pancreas. Sulfonylureas are the preferred
hypoglycemic drugs.
In a preferred embodiment, the present invention relates to an oral dosage
form comprising a unique combination of a biguanide and a sulfonylurea.
The biguanide is preferably metformin or buformin or a pharmaceutically
acceptable salt thereof such as metformin hydrochloride or the metformin
salts described in U.S. Pat. Nos. 3,957,853 and 4,080,472 which are
incorporated herein by reference. The sulfonylurea compound is preferably
glipizide as described in U.S. Pat. No. 5,545,413 or glyburide. Other
possible sulfonylurea compounds such as glibornuride, glisoxepide,
gliclazide acetohexamide, chlorpropamide, tolazamide, tolbutamide and
tolbutamide which are described in U.S. Pat. Nos. 5,674,900 and 4,708,868,
which are incorporated herein by reference, may also be employed.
The dosage form of the present invention can provide therapeutic levels of
the drugs from twelve to twenty-four hour periods. In a preferred
embodiment, the dosage form will be administered once a day and provide
therapeutic levels of the drug throughout the day.
In the prior art, many techniques have been used to provide controlled and
extended-release pharmaceutical dosage forms in order to maintain
therapeutic serum levels of medicaments and to minimize the effects of
missed doses of drugs caused by a lack of patient compliance.
In the prior art are extended release tablets which employ either a
biguanide drug alone or a sulfonylurea drug alone. For example WO 96/08243
discloses a controlled release dosage form containing only metformin HCl,
a biguanide, as the active ingredient and employs a hydrogel to push the
active ingredient from the dosage form. Similarly, U.S. Pat. Nos.
5,545,413, 5,591,454 and 5,091,190 disclose controlled release dosage
forms containing only the drug glipizide and employ a hydrogel to push the
active ingredient from the dosage form.
The 50th edition of the Physicians' Desk Reference.RTM., copyright 1996,
suggests administering to a patient a metformin HCl dosage form
commercially available from Bristol-Myers Squibb Co. under the tradename
GLUCOPHAGE.RTM. and a dosage form of a sulfonylurea compound such as
glyburide. More specifically, page 753 of the 50th edition of the
Physicians' Desk Reference states that if adequate glycemic control is not
attained with GLUCOPHAGE.RTM. monotherapy, the combination of
GLUCOPHAGE.RTM. and a sulfonylurea such as glyburide may have a
synergistic effect, since both active ingredients act to improve glucose
tolerance by different mechanism. According to the 50th edition of the
Physicians' Desk Reference, the GLUCOPHAGE.RTM. dosage form is believed to
function by decreasing hepatic glucose production, decreasing intestinal
absorption of glucose and improving insulin sensitivity, while the
sulfonylurea compound is believed to lower the blood glucose levels by
stimulating the release of insulin from the pancreas.
Although the 50th edition of the Physicians' Desk Reference suggests the
combined administration of metformin HCl and a sulfonylurea compound, it
fails to suggest a single unitary controlled release dosage form
comprising both an antihyperglycemic drug and a hypoglycemic drug that can
provide continuous and non-pulsating therapeutic levels of an
antihyperglycemic drug and a hypoglycemic drug to an animal in need of
such treatment over a twelve hour or twenty-four hour period.
It is an object of the present invention to provide a controlled or
sustained release formulation that contains both an antihyperglycemic drug
and a hypoglycemic drug.
It is a further object of the present invention to provide a controlled or
sustained release formulation that contains both an antihyperglycemic drug
and a hypoglycemic drug that does not employ an expanding or gel forming
material to push the drugs out.
It is a further object of the present invention to provide a controlled or
sustained release formulation that contains both an antihyperglycemic drug
and a hypoglycemic drug that can provide continuous and non-pulsating
therapeutic levels of an antihyperglycemic drug to an animal in need of
such treatment over a twelve hour or twenty-four hour period.
It is also an object of this invention to provide a controlled or sustained
release pharmaceutical tablet having a homogeneous core wherein the core
component may be made using ordinary tablet compression techniques.
SUMMARY OF THE INVENTION
The foregoing objectives are meet by a controlled release dosage form which
comprises:
(a) a core which comprises:
(i) an antihyperglycemic drug;
(ii) a hypoglycemic drug;
(iii) a binding agent; and
(iv) optionally, an absorption enhancer;
(b) optionally a seal coating layer around the core;
(c) a semipermeable coating membrane surrounding the core; and
(d) at least one passageway in the semipermeable membrane to allow release
of the antihyperglycemic drug and the hypoglycemic drug.
In the preferred embodiment the antihyperglycemic drug is a biguanide such
as metformin or a pharmaceutically acceptable salt and the hypoglycemic
drug is a sulfonylurea, such as glipizide or a pharmaceutically acceptable
salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph which depicts the dissolution profile in simulated
intestinal fluid (SIF), pH 7.5 phosphate buffer of the formulation
described in Example 1 as tested according to the procedure described in
United States Pharmacopeia XXIII, Apparatus 2 @ 75 rpm.
FIG. 2 is a graph which depicts the dissolution profile in simulated
intestinal fluid (SIF), pH 7.5 phosphate buffer of the formulation
described in Example 2 as tested according to the procedure described in
United States Pharmacopeia XXIII, Apparatus 2 @ 75 rpm.
DETAILED DESCRIPTION OF THE INVENTION
The term antihyperglycemic drug as used in this specification refers to
drugs that are useful in controlling or managing noninsulin-dependent
diabetes mellitus (NIDDM) by decreasing hepatic glucose production,
decreasing intestinal absorption of glucose and/or improving insulin
sensitivity. Preferably the antihyperglycemic drug is a biguanide such as
metformin or buformin or a pharmaceutically acceptable salt thereof such
as metformin hydrochloride.
The term hypoglycemic drug as used in this specification refers to drugs
that are useful in controlling or managing noninsulin-dependent diabetes
mellitus (NIDDM) by stimulating the release of insulin from the pancreas.
Preferably the hypoglycemic drug is a sulfonylurea compound such as
glyburide, glipizide, glibornuride, glisoxepide, gliclazide,
acetohexamide, chlorpropamide, tolazamide, tolbutamide, tolbutamide or
mixtures thereof.
The binding agent may be any conventionally known pharmaceutically
acceptable binder, but it is preferred that the binding agent be a
water-soluble polymer such as polyvinyl pyrrolidone having a weight
average molecular weight of 25,000 to 200,000. Other pharmaceutically
acceptable water-soluble polymers include hydroxypropyl cellulose,
hydroxyethyl cellulose, hydroxypropyl methylcellulose and the like.
Mixtures of the water-soluble binders may also be used. The water-soluble
binders comprise approximately about 0 to about 40% of the total weight of
the core and preferably about 3-15% of the total weight of the core.
The absorption enhancer employed in the core can be any type of absorption
enhancer commonly known in the art such as a fatty acid, a surfactant, a
chelating agent, a bile salt or mixtures thereof. Examples of some
preferred absorption enhancers are fatty acids such as capric acid, oleic
acid and their monoglycerides, surfactants, especially alkyl sulfates,
such as sodium lauryl sulfate, sodium dodecyl sulfate and polysorbate 80,
chelating agents such as citric acid and phytic acid. The core comprises
approximately 1 to about 20% absorption enhancer based on the total weight
of the core and most preferably about 2 to about 10% of the total weight
of the core.
The core of the present invention which comprises the antihyperglycemic
drug, the hypoglycemic drug, the binder which preferably is a
pharmaceutically acceptable water-soluble polymer and the absorption
enhancer is preferably formed by mixing and tableting techniques commonly
known in the art. The core may also be formed by granulating the core
ingredients and compressing the granules with or without the addition of a
lubricant into a tablet. The tableting can be performed on a rotary press.
Other commonly known excipients may also be included into the core such as
lubricants, pigments or dyes.
The homogeneous core is subsequently coated with a semipermeable membrane,
preferably a modified polymeric membrane to form the controlled release
tablet of the invention. The semipermeable membrane is permeable to the
passage of an external fluid such as water and biological fluids and is
impermeable to the passage of the antihyperglycemic drug and/or the
hypoglycemic drug in the core. Materials that are useful in forming the
semipermeable membrane are cellulose esters, cellulose diesters, cellulose
triesters, cellulose ethers, cellulose ester-ether, cellulose acylate,
cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose
diacetate, cellulose triacetate, cellulose acetate propionate, cellulose
acetate butyrate and ethylcellulose. Other suitable polymers are described
in U.S. Pat. Nos. 3,845,770, 3,916,899, 4,008,719, 4,036,228 and 4,11210
which are incorporated herein by reference. The most preferred
semipermeable membrane material is cellulose acetate comprising an acetyl
content of 39.3 to 40.3%, commercially available under the tradename CA
398-10 or CA 398-3 from Eastman Fine Chemicals.
In an alternative embodiment, the semipermeable membrane can be formed from
the above-described polymers and a flux enhancing agent. The flux
enhancing agent increase the volume of fluid imbibed into the core to
enable the dosage form to dispense substantially all of the
antihyperglycemic drug and hypoglycemic drug through both the passageway
and the porous membrane. The flux enhancing agent is a water-soluble
component such as sodium chloride, potassium chloride, sugar, sucrose,
sorbitol, mannitol, polyethylene glycol (weight av. molecular weight
380.about.3700), propylene glycol, hydroxypropyl cellulose, hydroxypropyl
methylcellulose and mixtures thereof. The preferred flux enhancer is PEG
400.
The flux enhancing agent comprises approximately 0 to 40% of the total
weight of the coating, most preferably 2-20% of the total weight of the
coating. The flux enhancing agent dissolves or leaches from the
semipermeable membrane to form paths in the semipermeable membrane for the
fluid to enter the core and dispense the active ingredients from the core.
The semipermeable membrane may also be formed with commonly known
excipients such a plasticizer. Some commonly known plasticizers include
adipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate,
triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citric
acid esters, and those described in the Encyclopedia of Polymer Science
and Technology, Vol. 10 (1969), published by John Wiley & Sons. The
preferred plasticizer is triacetin but materials such as acetylated
monoglyceride, rape seed oil, olive oil, sesame oil,
acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol,
diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate,
diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate,
tributylcitrate, glyceroltributyrate, and the like. Depending on the
particular plasticizer, amounts of from 0% to 25%, and preferably 2 to 15%
of the plasticizer can be used based upon the total weight of the coating.
As used herein the term passage way includes an aperture, orifice, bore,
hole, weaken area or an erodible element such as a gelatin plug that
erodes to form an osmotic passage way for the release of the
antihyperglycemic drug and hypoglycemic drug from the dosage form. A
detailed description of the passageway can be found in U.S. Pat. Nos.
3,845,770, 3,916,899, 4,034,758, 4,077,407, 4,783,337 and 5,071,607.
Generally, the membrane coating around the core will comprise from about
1-10% (theoretically) and preferably about 2-6% (theoretically) based on
the total weight of the core and coating.
In a preferred embodiment the dosage form will have the following
composition:
______________________________________
Preferred Most Preferred
______________________________________
CORE:
antihyperglycemic cpd
50-96% 75-93%
hypoglycemic cpd
0.05-3% 0.25-2%
binder 0-40% 3-15%
absorption enhancer
1-20% 2-10%
COATING:
semipermeable polymer
50-99% 75-95%
plasticizer 0-25% 2-15%
flux enhancer 0-40% 2-20%
______________________________________
The dosage forms prepared according to the present invention should exhibit
the following dissolution profile when tested in a USP type 2 (paddle)
apparatus at 75 rpms in 900 ml of simulated intestinal fluid (pH 7.5
phosphate buffer) and at 37.degree. C.:
______________________________________
ANTIHYPERGLYCEMIC RELEASE
Time (hours) Preferred
Most Preferred
______________________________________
2 0-30% 0-25%
4 10-50% 20-45%
8 30-90% 45-90%
12 NLT 50% NLT 60%
16 NLT 60% NLT 70%
______________________________________
NLT = NOT LESS THAN
______________________________________
HYPOGLYCEMIC RELEASE
Time (hours) Preferred
Most Preferred
______________________________________
2 0-30% 0-25%
4 10-50% 20-45%
8 30-90% 45-90%
12 NLT 50% NLT 60%
16 NLT 60% NLT 70%
______________________________________
NLT = NOT LESS THAN
In the preparation of the tablets of the invention, various conventional
well known solvents may be used to prepare the granules and apply the
external coating to the tablets of the invention. In addition, various
diluents, excipients, lubricants, dyes, pigments, dispersants etc. which
are disclosed in Remington's Pharmaceutical Sciences, 1995 Edition may be
used to optimize the formulations of the invention. In the alternative,
dry granulation techniques may be used to prepare the granules for making
compressed tablets.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
EXAMPLE 1
A once a day controlled release tablet containing 850 mg of metformin HCl
and 5 mg of glipizide and having the following formula is prepared as
follows:
______________________________________
I Core Weight %
______________________________________
metformin HCl 88.10%
glipizide 0.52%
povidone.sup.1, USP
6.33%
sodium lauryl sulfate
4.56%
magnesium stearate
0.50%
______________________________________
.sup.1 approximate molecular weight = 1,000,000; dynamic viscosity (10%
w/v solution at 20.degree. C.) = 300-700 mPa s.
(a) Granulation
1321.46 g of metformin HCl and 67.01 g of sodium lauryl sulfate are
delumped by passing the compounds through a 40 mesh screen and then mixed.
94.92 g of povidone, K-90, and 1.34 g of sodium lauryl sulfate are
dissolved in 1,803.5 g of purified water and then 7.76 g of glipizide is
dispersed in the solution. The mixture of metformin HCl and sodium lauryl
sulfate is then added to a top-spray fluidized bed granulator and
granulated by spraying with the granulating solution of povidone, sodium
lauryl sulfate and glipizide under the following conditions: product
temperature: 35-45.degree. C.; atomization pressure: 1-3 bar; spray rate:
10-150 ml/min. Once the granulating solution is depleted and the granules
are dried in the fluidized bed coater until the loss on drying is less
than 2%. The dried granules are then passed through a Comil equipped with
a screen equivalent to 18 mesh.
(b) Tableting
7.50 g of magnesium stearate is passed through a 40 mesh stainless steel
screen and blended with the metformin HCl/glipizide granules for
approximately five (5) minutes. After blending, the granules are
compressed on a rotary press fitted with 15/32" round standard concave
punches.
(c) Seal Coating (optional)
The tablet or core is seal coated with an Opadry material or other suitable
water-soluble material by first dissolving the Opadry material, preferably
Opadry clear in purified water. The Opadry solution is then sprayed onto
the tablet or core using a pan coater under the following conditions:
exhaust air temperature of 38-42.degree. C.; atomization pressure of 28-40
psi; and spray rate of 10-150 ml/min. The core tablets are coated with the
seal coating until a theoretical coating level of approximately 2% is
obtained.
______________________________________
II Sustained Release Coating
Weight %
______________________________________
cellulose acetate (398-10).sup.2
85%
triacetin 5%
PEG 400.sup.3 10%
______________________________________
.sup.2 acetyl content 39.3-40.3%
.sup.3 weight av. molecular weight 380-420
(d) Sustained Release Coating
The cellulose acetate is dissolved in acetone while stirring with a
homogenizer. The polyethylene glycol 400 and triacetin are added to the
cellulose acetate solution and stirred until a homogenous solution is
obtained. The coating solution is then sprayed onto the seal coated
tablets in a fluidized bed coter employing the following conditions:
product temperature of 15-25.degree. C.; atomization pressure of
approximately 1-2 bar; and a spray rate of 10-30 ml/min. This coating
process continues until a theoretical coating level of approximately 3% is
obtained.
Once the theoretical coating level is obtained, the sustained release
coated tablets are dried in the fluidized bed coater for approximately 5
to 10 minutes. Then one hole is either mechanically drilled or laser
drilled onto each side of the sustained release tablet.
The resulting tablets are tested in simulated intestinal fluid (pH 7.5)
according to the procedure described in United States Pharmacopeia XXIII,
Apparatus 2 (paddle) @ 75 rpm and found to have the following release
profile:
______________________________________
METFORMIN HCl RELEASE
TIME (hours) % Released (pH 7.5)
______________________________________
2 17
4 32
8 56
12 76
16 89
______________________________________
______________________________________
GLIPIZIDE RELEASE
TIME (hours) % Released (pH 7.5)
______________________________________
2 22
4 37
8 57
12 76
16 90
______________________________________
The release profile in simulated intestinal fluid (pH 7.5) of the sustained
release product prepared in this Example is shown in FIG. 1.
EXAMPLE 2
A controlled release tablet containing 500 mg of metformin HCl and 5 mg of
glipizide and having the following formula is prepared as follows:
______________________________________
I Core Weight %
______________________________________
metformin HCl 87.77%
glipizide 0.88%
povidone.sup.4, USP
6.31%
sodium lauryl sulfate
4.54%
magnesium stearate
0.50%
______________________________________
.sup.4 approximate molecular weight = 1,000,000 dynamic viscosity (10% w/
solution at 20.degree. C.) = 300-700 mPa s.
(a) Granulation
5.266 kg of metformin HCl and 0.263 kg of sodium lauryl sulfate are
delumped by passing the compounds through a 40 mesh screen and then mixed.
0.379 kg of povidone, K-90, 0.009 kg of sodium lauryl sulfate are
dissolved in 7.201 kg of purified water and then 0.053 kg of glipizide is
dispersed in the solution. The mixture of metformin HCl and sodium lauryl
sulfate is then added to a top-spray fluidized bed granulator and
granulated by spraying with the granulating solution of povidone, sodium
lauryl sulfate and glipizide under the following conditions: product
temperature: 35-45.degree. C.; atomization pressure: 1-3 bar; spray rate:
10-150 ml/min. Once the granulating solution is depleted and the granules
are dried in the fluidized bed coater until the loss on drying is less
than 2%. The dried granules are then passed through a Comil equipped with
a screen equivalent to 18 mesh.
(b) Tableting
The granules are pressed into tablets according to the procedure outlined
in Example 1 with the exception that 0.030 kg of magnesium stearate is
employed.
(c) Seal Coating (optional)
The tablets are seal coated with an Opadry material or other suitable
water-soluble material according to the procedure outlined in Example 1.
______________________________________
II Sustained Release Coating
Weight %
______________________________________
cellulose acetate (398-10).sup.5
85%
triacetin 5%
PEG 400.sup.6 10%
______________________________________
.sup.5 acetyl content 39.3-40.3%
.sup.6 weight av. molecular weight 380-420
(d) Sustained Release Coating
The sustained release coating solution is prepared and applied to the seal
coated tablets according to the procedure outlined in Example 1, with the
exception that the sustained release coating is applied to the seal coated
tablets until a theoretical coating level of approximately 4.5% is
obtained.
The resulting tablet is tested in simulated intestinal fluid (pH 7.5)
according to the procedure described in United States Pharmacopeia XXIII,
Apparatus 2 (paddle) @ 75 rpm and found to have the following release
profile:
______________________________________
METFORMIN HCl RELEASE
TIME (hours) % Released (pH 7.5)
______________________________________
2 23
4 41
8 70
12 92
16 98
______________________________________
______________________________________
GLIPIZIDE RELEASE
TIME (hours) % Released (pH 7.5)
______________________________________
2 23
4 35
8 56
12 75
16 90
______________________________________
The release profile in SIF of the sustained release product prepared in
this Example is shown in FIG. 2.
While certain preferred and alternative embodiments of the invention have
been set forth for purposes of disclosing the invention, modifications to
the disclosed embodiments may occur to those who are skilled in the art.
Accordingly, the appended claims are intended to cover all embodiments of
the invention and modifications thereof which do not depart from the
spirit and scope of the invention.
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